JPH034555B2 - - Google Patents
Info
- Publication number
- JPH034555B2 JPH034555B2 JP55047012A JP4701280A JPH034555B2 JP H034555 B2 JPH034555 B2 JP H034555B2 JP 55047012 A JP55047012 A JP 55047012A JP 4701280 A JP4701280 A JP 4701280A JP H034555 B2 JPH034555 B2 JP H034555B2
- Authority
- JP
- Japan
- Prior art keywords
- adca
- mol
- cephadroxil
- hydrate
- cooled
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- NVIAYEIXYQCDAN-CLZZGJSISA-N 7beta-aminodeacetoxycephalosporanic acid Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)[C@@H](N)[C@@H]12 NVIAYEIXYQCDAN-CLZZGJSISA-N 0.000 claims description 57
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 52
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 25
- 238000000034 method Methods 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 150000008064 anhydrides Chemical class 0.000 claims description 16
- 238000004519 manufacturing process Methods 0.000 claims description 14
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 229910001868 water Inorganic materials 0.000 claims description 10
- -1 ethoxyl Chemical group 0.000 claims description 8
- 239000012467 final product Substances 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000001240 enamine group Chemical group 0.000 claims description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 2
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 2
- 150000007522 mineralic acids Chemical class 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 48
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 35
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 33
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 25
- 229960004841 cefadroxil Drugs 0.000 description 22
- NBFNMSULHIODTC-CYJZLJNKSA-N cefadroxil monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=C(O)C=C1 NBFNMSULHIODTC-CYJZLJNKSA-N 0.000 description 22
- AVGYWQBCYZHHPN-CYJZLJNKSA-N cephalexin monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 AVGYWQBCYZHHPN-CYJZLJNKSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 239000000203 mixture Substances 0.000 description 17
- 230000002906 microbiologic effect Effects 0.000 description 13
- 238000002360 preparation method Methods 0.000 description 13
- WSWCOQWTEOXDQX-MQQKCMAXSA-M (E,E)-sorbate Chemical compound C\C=C\C=C\C([O-])=O WSWCOQWTEOXDQX-MQQKCMAXSA-M 0.000 description 12
- 229940075554 sorbate Drugs 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 10
- 238000004090 dissolution Methods 0.000 description 10
- KINULKKPVJYRON-PVNXHVEDSA-N n-[(e)-[10-[(e)-(4,5-dihydro-1h-imidazol-2-ylhydrazinylidene)methyl]anthracen-9-yl]methylideneamino]-4,5-dihydro-1h-imidazol-2-amine;hydron;dichloride Chemical class Cl.Cl.N1CCN=C1N\N=C\C(C1=CC=CC=C11)=C(C=CC=C2)C2=C1\C=N\NC1=NCCN1 KINULKKPVJYRON-PVNXHVEDSA-N 0.000 description 10
- 229940106164 cephalexin Drugs 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000000376 reactant Substances 0.000 description 9
- 206010037660 Pyrexia Diseases 0.000 description 8
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 239000008367 deionised water Substances 0.000 description 7
- 229910021641 deionized water Inorganic materials 0.000 description 7
- 238000004128 high performance liquid chromatography Methods 0.000 description 7
- LJCWONGJFPCTTL-UHFFFAOYSA-N 4-hydroxyphenylglycine Chemical compound OC(=O)C(N)C1=CC=C(O)C=C1 LJCWONGJFPCTTL-UHFFFAOYSA-N 0.000 description 6
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 6
- UQFHJDVUQSAVOQ-UHFFFAOYSA-N (2-aminophenyl) acetate Chemical compound CC(=O)OC1=CC=CC=C1N UQFHJDVUQSAVOQ-UHFFFAOYSA-N 0.000 description 5
- ZXNRTODJAQXKJX-STWYSWDKSA-N C(\C=C\C=C\C)(=O)O.CN(C=O)C Chemical compound C(\C=C\C=C\C)(=O)O.CN(C=O)C ZXNRTODJAQXKJX-STWYSWDKSA-N 0.000 description 5
- 150000002081 enamines Chemical class 0.000 description 5
- 230000007062 hydrolysis Effects 0.000 description 5
- 238000006460 hydrolysis reaction Methods 0.000 description 5
- 229910052700 potassium Inorganic materials 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- ZGUNAGUHMKGQNY-SSDOTTSWSA-N D-alpha-phenylglycine Chemical compound OC(=O)[C@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-SSDOTTSWSA-N 0.000 description 4
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000004448 titration Methods 0.000 description 4
- NMKSBNZBSLHAKW-UHFFFAOYSA-N Cl.ClO Chemical compound Cl.ClO NMKSBNZBSLHAKW-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000008034 disappearance Effects 0.000 description 3
- 239000012452 mother liquor Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- FEMOMIGRRWSMCU-UHFFFAOYSA-N ninhydrin Chemical compound C1=CC=C2C(=O)C(O)(O)C(=O)C2=C1 FEMOMIGRRWSMCU-UHFFFAOYSA-N 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000011403 purification operation Methods 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- 102100027324 2-hydroxyacyl-CoA lyase 1 Human genes 0.000 description 1
- NVIAYEIXYQCDAN-UHFFFAOYSA-N 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)C(N)C12 NVIAYEIXYQCDAN-UHFFFAOYSA-N 0.000 description 1
- CAQWNKXTMBFBGI-UHFFFAOYSA-N C.[Na] Chemical compound C.[Na] CAQWNKXTMBFBGI-UHFFFAOYSA-N 0.000 description 1
- LJCWONGJFPCTTL-SSDOTTSWSA-N D-4-hydroxyphenylglycine Chemical compound [O-]C(=O)[C@H]([NH3+])C1=CC=C(O)C=C1 LJCWONGJFPCTTL-SSDOTTSWSA-N 0.000 description 1
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 1
- 101001009252 Homo sapiens 2-hydroxyacyl-CoA lyase 1 Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 1
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 230000007815 allergy Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hcl hcl Chemical compound Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- UQEAIHBTYFGYIE-UHFFFAOYSA-N hexamethyldisiloxane Chemical compound C[Si](C)(C)O[Si](C)(C)C UQEAIHBTYFGYIE-UHFFFAOYSA-N 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- BHGADZKHWXCHKX-UHFFFAOYSA-N methane;potassium Chemical compound C.[K] BHGADZKHWXCHKX-UHFFFAOYSA-N 0.000 description 1
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Description
【発明の詳細な説明】
［産業上の利用分野］
本発明は構造（）
（式中Ｒは−Ｈまたは−OHである）
を有する７−アミノ−デスアセトキシセフアロス
ポラニツク酸（以下７−ADCAと称する）の誘
導体（derivatives of ７−amino−
desacetoxycephalosporanic acid）を製造する
方法に関する。[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a structure () derivatives of 7-amino-desacetoxycephalosporanic acid (hereinafter referred to as 7-ADCA) having the following formula:
The present invention relates to a method for producing desacetoxycephalosporanic acid.
［従来の技術］
米国特許明細書第3985741号は、構造式（）
のＲが−OHである（一般にセフアドロキシル
“cephadroxyl”と呼ばれる）化合物の製造につ
いて記載しており、これによればＰ−ヒドロキシ
フエニルグリシンデインソールトメチルソデイウ
ムとエチル−クロロフオルミエイト（ethyl−
chlorofotmiate）をＮ−メチルモルフオリンの存
在下反応させることによつて得られた混合無水物
と７−ADCAを反応させる事により、目的の化
合物を得ている。ここでデインソールとはアミノ
基がβ−ケトエステルとの縮合で保護された化合
物である。この方法は、ベルギー特許第853974号
にも記載されている通り、収率が低く工業的価値
がなく、かつ純度も低い。[Prior Art] U.S. Patent Specification No. 3985741 has the structural formula ()
describes the preparation of a compound in which R is -OH (commonly referred to as cephadroxyl), in which P-hydroxyphenylglycine deinsolet methyl sodium and ethyl chloroformiate (ethyl −
The target compound is obtained by reacting 7-ADCA with a mixed anhydride obtained by reacting chlorofotmiate) in the presence of N-methylmorpholine. Here, deinsole is a compound whose amino group is protected by condensation with β-ketoester. As described in Belgian Patent No. 853974, this method has low yield, no industrial value, and low purity.
上記ベルギー特許に第853974号にはセフアドロ
キシルの製造方法として、塩酸のアクセプターと
してのジメチルアニリンの存在下、７−ADCA
のケイ酸エステルがＰ−ヒドロキシフエニルグリ
シンクロライドクロロハイドレイトエミジオキサ
ンソルヴエイト（Ｐ−hydroxy−phenylglycine
chlooride−chlorohydrate、emidioxan
solvate）と反応させる方法が記載されており、
好収率を示しているが、この方法は最終生成物が
不純物としてジメチルアニリンやヘキサメチルジ
シロキサン等のシリコンの有機誘導体を含むとい
う問題が有る。 The Belgian patent No. 853974 describes a method for producing cephadroxil using 7-ADCA in the presence of dimethylaniline as an acceptor for hydrochloric acid.
The silicate ester is P-hydroxy-phenylglycine chloride chlorohydrate emidioxane sorbate
chloride−chlorohydrate, emidioxan
solvate) is described,
Although good yields have been shown, this method has the problem that the final product contains organic derivatives of silicon such as dimethylaniline and hexamethyldisiloxane as impurities.
さらに、Ｐ−ヒドロキシフエニルグリシンのク
ロライドクロロハイドレイドにより不純物として
重合物質を生じ、セフアドロキシルを治療薬に用
いた際、アレルギーを引起こす可能性がある。 Furthermore, the chloride chlorohydride of P-hydroxyphenylglycine produces polymeric substances as impurities, which may cause allergies when cephadroxil is used as a therapeutic agent.
欧州特願第1133号はセフアドロキシルを製造す
る方法として、メチレンクロライドまたはメチル
イソブチルケトンと他の溶媒からなる混合溶媒
中、Ｎ−メチルモルフオリンの存在下、Ｐ−ヒド
ロキシフエニルグリシンデインソールトメチルカ
リウムとメチルクロロフオルメイトを反応させて
得られた混合無水物を、７−ADCAのケイ酸エ
ステルと反応させる方法が記載されているが、こ
の方法はセフアドロキシルにヘキサメチルジシロ
キサン等７−ADCAのキシリル（xylil）誘導体
に起因する不純物を生じ、この不純物が水に不溶
性で除去が困難である。 European Patent Application No. 1133 discloses a method for producing cephadroxil, in which P-hydroxyphenylglycine deinsolte methylpotassium is used in the presence of N-methylmorpholine in a mixed solvent of methylene chloride or methyl isobutyl ketone and other solvents. A method is described in which a mixed anhydride obtained by reacting 7-ADCA with silicate ester of 7-ADCA is reacted with cephadroxil and methyl chloroformate. (xylil) derivatives, which are insoluble in water and difficult to remove.
また構造式（）の化合物（一般にセフアレキ
シン“cephalexine”と呼ばれる）については米
国特許第3507861号、第3671449号、第3634416号
及び第3676437号にその製造方法が記載されてい
る。 Furthermore, methods for producing the compound of structural formula () (generally referred to as cephalexine) are described in US Pat.
［発明が解決しようとする問題点］
従来の製法で用いられている、例えばシリラン
テイング（sililanting）剤やＰ−ヒドロキシフエ
ニルグリシンクロライドクロロハイドレイトはコ
スト的には高価である。また、７−ADCAの保
護基（２，２，２−トリクロロエチル、Ｐ−ニト
ロベンジルまたはトリメチルシリル等）をはずす
操作は最終生成物の低純度を招いてしまう。[Problems to be Solved by the Invention] For example, sililanting agents and P-hydroxyphenylglycine chloride chlorohydrate used in conventional production methods are expensive. Furthermore, the operation of removing the protective group (2,2,2-trichloroethyl, P-nitrobenzyl, trimethylsilyl, etc.) from 7-ADCA leads to a low purity of the final product.
以上の様に従来の７−ADCAの誘導体の製造
は低収率、低純度であつて精製操作が必要であつ
たり、コスト的に問題が有る事、工業生産に不適
当であるのが現状である。 As mentioned above, the conventional production of 7-ADCA derivatives is low yield, low purity, requires purification operations, has cost problems, and is unsuitable for industrial production. be.
本発明はコストのかかる化合物を用いず、高収
率で高純度の７−ADCAの誘導体を製造する方
法である。 The present invention is a method for producing 7-ADCA derivatives in high yield and purity without using costly compounds.
［問題点を解決するための手段及び作用］
本発明は、前述の構造式（）を有する７−
ADCAの誘導体の製造方法であり、詳しくはジ
メチルホキサイド、ジメチルアセトアミド、ホル
ムアミド、ジメチルホルムアミドから選ばれる一
種を溶媒とし、水の存在下、０℃〜20℃
温度で、７−ADCAを７−ADCA1molに対し
1.05〜1.25molのトリエチルアミン（以下TEAと
略称する）で処理して得られた溶液に、構造式
（）
式中、Ｒは−Ｈまたは−OHであり、R1はメチ
ル、エチルまたはイソブチルであり、そして
R2はメトキシルまたはエトキシルである。[Means and effects for solving the problems] The present invention provides 7-
This is a method for producing a derivative of ADCA. Specifically, 7-ADCA is converted into 7-ADCA by 1 mol of 7-ADCA in the presence of water at a temperature of 0°C to 20°C using a solvent selected from dimethyl oxide, dimethylacetamide, formamide, and dimethylformamide. against
The structural formula () where R is -H or -OH, R1 is methyl, ethyl or isobutyl, and
R 2 is methoxyl or ethoxyl.
を有する、少なくとも７−ADCAと等mol量の混
合無水物を加えこの混合後の温度が−60℃〜−10
℃になるように維持し、次にこの反応混合体に無
機酸の水溶液を加えてPHを0.8〜2.5に下げてエナ
ミン基を分離し、最終生成物を既知の方法で分離
して目的の７−ADCAの誘導体を得る。At least 7-ADCA and an equimolar amount of mixed anhydride having
The enamine group is separated by adding an aqueous solution of an inorganic acid to this reaction mixture to lower the pH between 0.8 and 2.5, and the final product is separated by known methods to give the desired 7 - Obtaining a derivative of ADCA.
構造式（）の混合無水物は好ましくはそれぞ
れのデインソールトをクロロホルメイト（好まし
くはエチルクロロホルメイト）とアセトン中、Ｎ
−メチルモルフオリンの存在下、−60℃〜−20℃
の範囲の温度で反応させる。この方法は例えば米
国特許第3985741号に記載されている方法で良い。 Mixed anhydrides of structural formula () are preferably prepared by combining each deinsault with a chloroformate (preferably ethyl chloroformate) in acetone with N
−60°C to −20°C in the presence of methylmorpholine
The reaction is carried out at a temperature in the range of . This method may be, for example, the method described in US Pat. No. 3,985,741.
さらに、７−ADCAの溶媒は７−ADCA1mol
に対し10〜25molの量が好ましい。 Furthermore, the solvent for 7-ADCA is 1 mol of 7-ADCA.
An amount of 10 to 25 mol is preferable.
構造式（）の化合物は既に良く知られた化合
物であり、米国特許第3985741号や英国特許第
1327270号に記載されている。 The compound of structural formula () is already a well-known compound, and has been published in US Patent No. 3985741 and British Patent No.
Described in No. 1327270.
本発明者等は、構造式（）を有する化合物の
製造方法として、アセトンまたはアセトンと本発
明に用いる溶媒との混合溶媒中の構造式（）の
無水物と、水溶液中の７−ADCAとを反応させ
てみたが、収率が非常に低く工業生産には適して
いなかつた。 The present inventors have developed a method for producing a compound having the structural formula () by using an anhydride of the structural formula () in acetone or a mixed solvent of acetone and the solvent used in the present invention, and 7-ADCA in an aqueous solution. I attempted a reaction, but the yield was very low and it was not suitable for industrial production.
本発明者等は上記製造方法を詳細に検討し、７
−ADCAを特定の水性混合物中に溶解し、次い
で構造式（）の混合溶液に加える事により、非
常に高収率で７−ADCA誘導体が得られる事を
発見し、本発明を達成した。 The present inventors studied the above manufacturing method in detail, and 7
The present invention was accomplished by discovering that -ADCA can be dissolved in a specific aqueous mixture and then added to a mixed solution of structural formula () to obtain a 7-ADCA derivative in very high yield.
さらに、反応に用いられるTEAの量が７−
ADCA1molに対し、1.05〜1.25molの範囲の時の
み高収率である事がわかつた。 Furthermore, the amount of TEA used in the reaction is 7-
It was found that the yield was high only when the amount was in the range of 1.05 to 1.25 mol per 1 mol of ADCA.
構造式（）のＲが−OHである化合物の場
合、従来の方法では合成反応の終りに、未反応の
７−ADCAを除去するために過の操作が必要
であり、また、低収率で低純度であるため精製操
作が必要となるが、本発明の製法では７−
ADCAは完全に反応し高純度でも高収率の最終
生成物を得る。 In the case of a compound in which R in the structural formula () is -OH, conventional methods require an over-treatment at the end of the synthesis reaction to remove unreacted 7-ADCA, and the yield is low. Due to its low purity, purification operations are required, but in the production method of the present invention, 7-
ADCA reacts completely to obtain the final product in high yield even with high purity.
また、デインソールトそしてそれに応じた混合
無水物の技術は英国特許第1327270号及び米国特
許明細書第3694437号に記載されている。 Deinsault and corresponding mixed anhydride technology is also described in British Patent No. 1,327,270 and US Pat. No. 3,694,437.
［実施例］
以下、本発明を実施例により具体的に説明す
る。[Example] Hereinafter, the present invention will be specifically explained with reference to Examples.
実施例 １
(a) エトキシカルボニルＤ−α−（１−カルボメ
トキシ−プロペニル）アミノ−ｐ−ハイドロキ
シフエニルアセテイトの調製
２の反応フラスコに250mlの無水アセトンを
入れ−40℃に冷却し、次いで45.5ｇ（0.15モル）
のＤ（−）−Ｐ−ヒドロキシフエニルグリシンのカ
リウムメチルデインソールトを加え、さらに−40
℃で撹拌下16.7ｇ（0.1545モル）のエチルクロロ
ホルムメイト（ethyl chloroformiate）と0.4ml
のＮ−メチルモルフオリンを加えた。発熱は−35
℃以内で、−35℃で２時間反応させた。この反応
混合体を−55℃に冷却した。Example 1 (a) Preparation of ethoxycarbonyl D-α-(1-carbomethoxy-propenyl)amino-p-hydroxyphenylacetate 250 ml of anhydrous acetone was placed in the reaction flask from 2, cooled to -40°C, and then 45.5g (0.15mol)
of D(-)-P-hydroxyphenylglycine, and then -40
16.7 g (0.1545 mol) ethyl chloroformiate and 0.4 ml under stirring at °C.
of N-methylmorpholine was added. Fever is -35
The reaction was carried out at -35°C for 2 hours. The reaction mixture was cooled to -55°C.
(b) ７−ADCAの溶解
１の反応フラスコ中に75mlの脱イオン水と
32.1ｇ（0.15モル）の７−ADCAと135mlのジメ
チルスルホキサイドを−15℃で加え、次いで16.9
ｇ（0.167モル）のTEAを15分間で加えた。７−
ADCAを溶解し（PHは10以下に保持する）、次い
で溶液を０℃に冷却した。(b) Dissolution of 7-ADCA In reaction flask 1, add 75 ml of deionized water and
32.1 g (0.15 mol) of 7-ADCA and 135 ml of dimethyl sulfoxide were added at -15°C, then 16.9
g (0.167 mol) TEA was added over 15 minutes. 7-
The ADCA was dissolved (PH kept below 10) and the solution was then cooled to 0°C.
(c) ジメチルホルムアミド（以下DMFと略称す
る）のセフアドロキシルソルベイト
（Cephadroxyl solvate）
(a)で調製した混合無水物のサスペンジヨンを−
55℃に冷却し、(b)で調整した７−ADCAの溶液
に加えた。発熱は−25℃以内であつた。次いで、
この混合物を−25℃で１時間撹拌した。１mlの反
応混合物を取り出し水で10mlに希釈し、GF254プ
レート30、50、100mlをスタンダードの７−
ADCA及びスタンダードのセフアドロキシルと
比較して置かれ、そして溶離は25mlCH3CN：４
mlH2O：２mlHCOOHで実施した。検出はニンヒ
ドリンで７−ADCAの消滅とセフアドロキシル
のスポツトの出現を観察した。(c) Cephadroxyl solvate in dimethylformamide (hereinafter abbreviated as DMF) The suspension of the mixed anhydride prepared in (a) -
It was cooled to 55°C and added to the 7-ADCA solution prepared in (b). The fever was within -25°C. Then,
This mixture was stirred at -25°C for 1 hour. Take 1 ml of the reaction mixture and dilute it to 10 ml with water.
ADCA and standard cephadroxil were compared and elution was carried out in 25ml CH3CN:4
mlH2O : Performed with 2ml HCOOH. For detection, the disappearance of 7-ADCA with ninhydrin and the appearance of cephadroxil spots were observed.
温度を０℃に上げ、エナミンの加水分解を37％
HClの溶液を加えPHを1.8に一定に保つことによ
つて始めた。一定のPH1.8で、260mlのメチレンク
ロリドを加え、10分間撹拌し、次いでデカント
し、メチレンクロライドとアセトンを含んでいる
下層を廃棄し、他方セフアドロキシルを含む上層
はHPLC（High Pressure Liquid
Chromatography）で分析し、理論的に97％以上
の変換が明らかになつた。このようにして得られ
たこの濃水を25mlのDMF及び100mlのアセトンと
混合して０℃でTEAをPH6.5になるよう滴下し、
次いで結晶化を0.5ｇのDMFのセフアドロキシル
ソルベイトで準備、もしくは結晶種を入れ、０℃
で２時間後結晶状生成物を得、過し、フイルタ
ー上100mlのDMFとH2O（１：１）の混合物で、
次いで100mlのアセトンで洗浄した。得られた生
成物は40℃で乾燥した。 Raise the temperature to 0℃ and hydrolyze enamine by 37%
Started by adding a solution of HCl and keeping the PH constant at 1.8. At a constant pH of 1.8, add 260 ml of methylene chloride, stir for 10 minutes, then decant and discard the lower layer containing methylene chloride and acetone, while the upper layer containing cephadroxil is purified by HPLC (High Pressure Liquid
Chromatography) analysis revealed a theoretical conversion of over 97%. The concentrated water thus obtained was mixed with 25 ml of DMF and 100 ml of acetone, and TEA was added dropwise at 0°C to adjust the pH to 6.5.
Crystallization was then prepared with 0.5 g of DMF of cephadroxil sorbate or seeded at 0°C.
After 2 hours a crystalline product was obtained, filtered and filtered with 100 ml of a mixture of DMF and H 2 O (1:1).
It was then washed with 100ml of acetone. The obtained product was dried at 40°C.
58.8ｇのセフアドロキシルDMFソルベイトが
得られ、理論的に90％に等しい。 58.8 g of cephadroxil DMF sorbate was obtained, equal to 90% of theory.
TLC：単一スポツト
［α］D＝＋122゜（on dry base）
K.F.＝1.8％
DMF（GLCで）＝16.2％
(d) セフアドロキシル−水和物の調製
(c)で得られたソルベイトを100mlのH2Oと混合
し、40℃で撹拌した。40℃で30分後、この混合物
を０℃に冷却し、そして結晶化２時間後過し、
30mlの氷水で洗浄、40℃で乾燥し、41.5ｇのセフ
アドロキシル−水和物を得た。 TLC: single spot [α] D = +122° (on dry base) KF = 1.8% DMF (in GLC) = 16.2% (d) Preparation of cephadroxil-hydrate (c) Add 100 ml of the sorbate obtained in Mixed with H 2 O and stirred at 40°C. After 30 minutes at 40°C, the mixture was cooled to 0°C and filtered after 2 hours of crystallization.
The mixture was washed with 30 ml of ice water and dried at 40°C to obtain 41.5 g of cephadroxil hydrate.
K.F.＝5.8％
［α］D＝＋168゜（on dry base）
微生物学的titer 933mcｇ／ｍｇ
母液を過し250mlのDMFで希釈し、生成物を
結晶化して過した。3.6ｇのセフアドロキシル
DMFソルベイトが得られ、これは上述の如く変
換し2.5ｇのセフアドロキシル−水和物（［α］D
＝＋165゜on dry base）を得た。前で得られた
41.5ｇと一緒にすると44ｇとなり、出発物質の７
−ADCAに対し77.0％の収率となつた。 KF = 5.8% [α] D = +168° (on dry base) Microbiological titer 933 mcg/mg The mother liquor was filtered and diluted with 250 ml of DMF, and the product was crystallized and filtered. 3.6g Cephadroxil
DMF sorbate was obtained, which was converted as described above to give 2.5 g of cephadroxil-hydrate ([α] D
= +165°on dry base) was obtained. obtained in front
When combined with 41.5g, it becomes 44g, which is 7 of the starting material.
-The yield was 77.0% based on ADCA.
実施例 ２
(a) エトキシカルボニルＤ−α−（１−カルボメ
トキシ−プロペニル）アミノＰ−ハイヒドロキ
シフエニルアセテイトの調製
280mlの無水アセトンを反応フラスコに入れ、−
45℃に冷却した後、47.6ｇ（0.157モル）のＤ
（−）Ｐ−ヒドロキシフエニルグリシンデインソ
ールトカリウムメチルを加え、さらに−45℃で、
17.57ｇ（0.162モル）のエチルクロロフオルメイ
トと0.4mlのＮ−メチルモルフオリンを加えた。
発熱は−30℃以内であり、反応は−30℃で２時間
行つた。この反応混合体を−50℃に冷却した。Example 2 (a) Preparation of ethoxycarbonyl D-α-(1-carbomethoxy-propenyl)amino P-hyhydroxyphenylacetate 280 ml of anhydrous acetone was placed in a reaction flask and -
After cooling to 45°C, 47.6 g (0.157 mol) of D
Add (-)P-hydroxyphenylglycine deinsolate potassium methyl, and further at -45°C,
17.57 g (0.162 mol) of ethyl chloroformate and 0.4 ml of N-methylmorpholine were added.
The exotherm was within -30°C and the reaction was carried out at -30°C for 2 hours. The reaction mixture was cooled to -50°C.
(b) ７−ADCAの溶解
DMSOのかわりに130mlのホルムアミドを用い
ることを除いて、実施例１の(b)で述べたと同じ方
法で行つた。(b) Dissolution of 7-ADCA This was carried out in the same manner as described in Example 1 (b), except that 130 ml of formamide was used instead of DMSO.
(c) DMFのセフアドロキシルソルベイト
実施例１の(c)で述べたと同じ方法と同じ量の反
応物質を用いた。(c) Cephadroxil sorbate in DMF The same method and the same amounts of reactants as described in Example 1 (c) were used.
この濃水溶液をHPLCで分析し97％の変換が認
められた。59.5ｇのセフアドロキシルDMFソル
ベイトが分離され、収量は90.9％であつた。 This concentrated aqueous solution was analyzed by HPLC and 97% conversion was observed. 59.5 g of cephadroxil DMF sorbate was isolated with a yield of 90.9%.
［α］D＝＋122゜
K.F.＝２％
(d) セフアドロキシル−水和物の調製
実施例１の(d)に記載されたと同じ方法に従つて
同じ量を用い、総量45.5ｇのセフアドロキシル−
水和物が得られた。 [α] D = +122° KF = 2% (d) Preparation of cephadroxil-hydrate Following the same method as described in Example 1 (d) and using the same amount, a total amount of 45.5 g of cephadroxil-
A hydrate was obtained.
微生物学的titer 928mcｇ／mg
［α］D＝＋173゜（on dry base）
収量 79.6％
実施例 ３
(b)の段階においてDMSOの換りに120mlの
DMFを用いることを除いて、実施例１に記載さ
れたと同じ方法と量が用いられた。44ｇのセフア
ドロキシル−水和物が得られた。 Microbiological titer 928 mcg/mg [α] D = +173° (on dry base) Yield 79.6% Example 3 In step (b), 120 ml of DMSO was used instead of DMSO.
The same methods and amounts as described in Example 1 were used, except that DMF was used. 44 g of cephadroxil hydrate were obtained.
［α］D＝＋170゜（on dry base）
K.F.＝5.8％
微生物学的titer 932mcｇ／mg
実施例 ４
(a) エトキシカルボニルＤ−α−（１−カルボメ
トキシ−プロペニル）アミノＰ−ハイヒドロキ
シフエニルアセテイトの調製
実施例１の(a)に記載されたと同じ量と方法が用
いられた。この混合無水物のサスペンジヨンを−
45℃に冷却した。 [α] D = +170° (on dry base) KF = 5.8% Microbiological titer 932mcg/mg Example 4 (a) Ethoxycarbonyl D-α-(1-carbomethoxy-propenyl)amino P-hyhydroxyphenyl Preparation of acetate The same amounts and method as described in Example 1(a) were used. This mixed anhydride suspension-
Cooled to 45°C.
(b) ７−ADCAの溶解
DMSOのかわりに130mlのジメチルホルムアミ
ドを用いることを除いて、実施例１の(b)に記載さ
れたと同じ方法と量が用いられた。(b) Dissolution of 7-ADCA The same method and amounts as described in Example 1 (b) were used, except that 130 ml of dimethylformamide was used instead of DMSO.
(c) セフアドロキシル−水和物の調製
(b)で調整された７−ADCAの溶液を−45℃に
冷却した(a)で調製された混合無水物のサスペンジ
ヨンに加えた。発熱は−25℃以内であつた。次い
で−25℃で１時間反応を行い、溶液の一部からセ
フアドロキシルの生成と出発物質７−ADCAの
消滅が示された。(c) Preparation of cephadroxil-hydrate The solution of 7-ADCA prepared in (b) was added to the mixed anhydride suspension prepared in (a) cooled to -45°C. The fever was within -25°C. The reaction was then carried out at -25°C for 1 hour, and a portion of the solution showed the formation of cephadroxil and the disappearance of the starting material 7-ADCA.
温度を０℃に上げ、エナミンの加水分解を37％
HClの溶液をPHが一定の2.0になるように加える
ことによつて（更に０℃で）始めた。一定のPH
2.0で260mlのメチレンクロライドを加え、次いで
10分間撹拌し、デカントした。メチレンクロライ
ドとアセトンを含む下層は捨て、他方セフアドロ
キシルを含む上層をHPCLで分析し、理論的に95
％の変換が見出された。 Raise the temperature to 0℃ and hydrolyze enamine by 37%
Begin by adding a solution of HCl (also at 0° C.) such that the pH is constant at 2.0. constant PH
Add 260ml methylene chloride at 2.0, then
Stir for 10 minutes and decant. The lower layer containing methylene chloride and acetone was discarded, while the upper layer containing cephadroxil was analyzed by HPCL.
% conversion was found.
このようにして得られた水層をデカライト
（dicalite）上、25℃で過し、PHはTEAで５に
し、結晶化を0.5ｇのセフアドロキシル−水和物
を種として行い、２時間撹拌後、過して23ｇの
セフアドロキシル−水和物が得られた。 The aqueous layer thus obtained was filtered over dicalite at 25°C, the pH was brought to 5 with TEA, and the crystallization was carried out seeded with 0.5 g of cephadroxil-hydrate and after stirring for 2 hours. 23 g of cephadroxil hydrate was obtained.
［α］D＝＋172゜（on dry base）
K.F.＝6.2％
微生物学的titer 929mcｇ／mg
収量 40.2％
母液を過し300mlのDMFを加え、セフアドロ
キシルジメチルフオルムアミドソルベイトを結晶
化させ過によつて集め、乾燥して、32.5ｇのジ
メチルフオルムアミドソルベイトが得られた。 [α] D = +172゜ (on dry base) KF = 6.2% Microbiological titer 929mcg/mg Yield 40.2% Strain the mother liquor and add 300ml of DMF to crystallize cefadroxil dimethylformamide sorbate. It was collected and dried to obtain 32.5 g of dimethyl formamide sorbate.
［α］D＝＋172゜（on dry base）
K.F.＝6.2％
微生物学的titer 929mcｇ／mg
収量 40.2％
母液を過し300mlのDMFを加え、セフアドロ
キシルジメチルフオルムアミドソルベイトを結晶
化し、過により集めて乾燥し、32.5ｇのジメチ
ルフオルムアミドソルベイトが得られた。 [α] D = +172゜ (on dry base) KF = 6.2% Microbiological titer 929mcg/mg Yield 40.2% Strain the mother liquor and add 300ml of DMF to crystallize cefadroxil dimethyl formamide sorbate, and filtrate. The mixture was collected and dried to obtain 32.5 g of dimethyl formamide sorbate.
［α］D＝＋121゜
K.F.＝1.8％
実施例１の(d)に記載された方法に従つた変換に
よつて、22.9ｇのセフアドロキシル−水和物が得
られた。 [α] D = +121° KF = 1.8% By conversion according to the method described in Example 1 (d), 22.9 g of cephadroxil hydrate were obtained.
［α］D＝＋173゜
K.F.＝5.8％
微生物学的titer 928mcｇ／mg
総収量は45.9ｇでそれは理論量の80.3％であ
る。 [α] D = +173° KF = 5.8% Microbiological titer 928 mcg/mg The total yield was 45.9 g, which was 80.3% of the theoretical amount.
実施例 ５
(b)段階で18.75ｇ（0.185モル）のTEAが７−
ADCAの溶解に用いられることを除いて、実施
例１で述べられたと同じ方法が行われそして同じ
量の反応物質が用いられた。Example 5 In step (b), 18.75 g (0.185 mol) of TEA was added to 7-
The same method as described in Example 1 was performed and the same amounts of reactants were used, except that ADCA was used to dissolve.
44ｇのセフアドロキシル−水和物が得られた。 44 g of cephadroxil hydrate were obtained.
収量 76.9％
［α］D＝＋171゜（on dry base）
K.F.＝６％
titer HPLC 98.9％（on dry base）
実施例６
(b)段階で16.2ｇ（0.160モル）のTEAが７−
ADCAの溶解に用いられることを除いて、実施
例１で述べられたと同じ方法が行われ、そして同
じ量の反応物質が用いられた。 Yield 76.9% [α] D = +171° (on dry base) KF = 6% titer HPLC 98.9% (on dry base) Example 6 In step (b), 16.2 g (0.160 mol) of TEA was added to 7-
The same method as described in Example 1 was performed and the same amounts of reactants were used, except that ADCA was used to dissolve.
44.5ｇのセフアドロキシル−水和物が得られ
た。 44.5 g of cephadroxil hydrate was obtained.
収量 77.8％
微生物学的titer 930mcｇ／mg
上述の実施例に従つて、以下の平均分析特性を
有するセフアドロキシル−水和物が得られた。 Yield 77.8% Microbiological titer 930 mcg/mg According to the above example, cephadroxil-hydrate was obtained with the following average analytical properties:
外観：白色結晶状粉末
I.R.：スタンダードと一致
水分：6.1％
PH 100mg／ml：4.5
Jiodometrical titer
：98.5％（on dry material）
分光光度計測定260μ：99.2％（ 〃 ）
H.P.L.C.titer：99.8％（ 〃 ）
施光度［α］D：＋172゜（ 〃 ）
酸滴定：100.5％（ 〃 ）
アミノ滴定：99％ （ 〃 ）
微生物学的：930mcｇ／mg
毒性：無毒性
安定性65℃／７日間：922mcｇ／mg
溶媒（GLC）
ジメチルアニリン：検出されず
メチレンクロライド：0.06％
TEA：0.05％
アセトン：0.1％
実施例 ７
(a) エトキシカルボニルＤ−α−（１−カルボメ
トキシル）アミノフエニルアセテイトの調製
反応フラスコに250mlの無水アセトン（K.F.0.1
％）を、次いで43ｇ（0.15モル）のＤ（−）フエ
ニルグリシンのカリウムメチルデインソールトを
入れ、−40℃に冷却し、16.7ｇ（0.1545モル）の
エチルクロロホルメイト、次いで0.3mlのＮ−メ
チルモルフオリンを加えた。発熱は−30℃以内で
あつた。この混合体を−30℃で２時間撹拌した。
この混合無水物のサスペンジヨンを−50℃に冷却
した。Appearance: White crystalline powder IR: Same as standard Moisture: 6.1% PH 100mg/ml: 4.5 Jiodometrical titer: 98.5% (on dry material) Spectrophotometer measurement 260μ: 99.2% (〃) HPLCtiter: 99.8% (〃) Luminous intensity [α] D : +172° (〃) Acid titration: 100.5% (〃) Amino titration: 99% (〃) Microbiological: 930mcg/mg Toxicity: Non-toxic stability 65℃/7 days: 922mcg/mg Solvent (GLC) Dimethylaniline: Not detected Methylene chloride: 0.06% TEA: 0.05% Acetone: 0.1% Example 7 (a) Preparation of ethoxycarbonyl D-α-(1-carbomethoxyl)aminophenyl acetate In the reaction flask 250ml anhydrous acetone (KF0.1
%), then 43 g (0.15 mol) of D(-)phenylglycine potassium methyldeinsault, cooled to -40°C, 16.7 g (0.1545 mol) of ethyl chloroformate, then 0.3 ml of N-methylmorpholine was added. The fever was within -30°C. This mixture was stirred at -30°C for 2 hours.
The mixed anhydride suspension was cooled to -50°C.
(b) ７−ADCAの溶解
80mlの脱イオン水を反応フラスコ中に導入し、
次いで32.1ｇ（0.15モル）の７−ADCA及び130
mlのDMSOを加えた。15℃で16.9ｇ（0.167モル）
のTEAを７−ADCAを溶解しながら加え、溶液
のPHを10にコントロールして、０℃に冷却した。(b) Dissolution of 7-ADCA 80 ml of deionized water was introduced into the reaction flask,
Then 32.1 g (0.15 mol) of 7-ADCA and 130
ml of DMSO was added. 16.9g (0.167mol) at 15℃
of TEA was added while dissolving 7-ADCA, the pH of the solution was controlled at 10, and the solution was cooled to 0°C.
(c) セフアレキシン−水和物（Cephalexine
monohydrate）
(a)で調製し、−50℃に冷却した混合無水物のサ
スペンジヨンを(b)で調製した７−ADCAの溶液
と素早く混合した。発熱は−30℃以内であつた。
この混合物を−30℃で１時間撹拌した。この溶液
の一部を取出しTLC（溶出液として25mlの
CH3CN：４mlのH2O：２mlのHCOOHを用いて）
にかけた。１mlの溶液は脱イオン水で10mlに希釈
し、30、50、100mlをGF254プレート上に比較の
スタンダードの７−ADCA及びセフアレキシン
と共にスポツトし、展開、ニンヒドリンで検出し
た。セフアレキシンの生成と７−ADCAの消滅
が観察された。(c) Cephalexine hydrate
The mixed anhydride suspension prepared in (a) and cooled to -50°C was quickly mixed with the solution of 7-ADCA prepared in (b). The fever was within -30°C.
This mixture was stirred at -30°C for 1 hour. Take a portion of this solution and perform TLC (25 ml as eluent).
CH3CN : using 4ml H2O : 2ml HCOOH)
I put it on. One ml of the solution was diluted to 10 ml with deionized water, 30, 50, and 100 ml were spotted on GF254 plates with comparison standards 7-ADCA and cephalexin, developed, and detected with ninhydrin. Production of cephalexin and disappearance of 7-ADCA were observed.
温度を０℃に上げ、次いで37％塩酸の溶液の添
加によつてエナミンの加水分解を行つた。加水分
解が完了した後、一定のPH1.8で、200mlのメチレ
ンクロライドを加え、次いで10分間撹拌し、30分
間デカントした。メチレンクロライドとアセトン
を含んでいる下層を廃棄し、他方濃水の上層は
HPLCにかけ、セフアレキシン−水和物として90
％の変換が示された。水層に50mlのメタノールを
加え、30℃に加熱し、PHをTEAで4.3に調節し、
生成物が結晶化するよう200mlのアセトンを加え、
15℃に冷却し、２時間撹拌後過し、100mlの
水：アセトン１：１で洗浄し、40℃で乾燥した。
45ｇのセフアレキシン−水和物が得られ。 The temperature was raised to 0° C. and the enamine was then hydrolyzed by addition of a solution of 37% hydrochloric acid. After the hydrolysis was completed, at a constant pH of 1.8, 200 ml of methylene chloride was added, then stirred for 10 minutes and decanted for 30 minutes. Discard the lower layer containing methylene chloride and acetone, while the upper layer of concentrated water
Cephalexin-hydrate as 90% by HPLC
% conversion indicated. Add 50ml of methanol to the aqueous layer, heat to 30℃, adjust the pH to 4.3 with TEA,
Add 200 ml of acetone so that the product crystallizes,
The mixture was cooled to 15°C, stirred for 2 hours, filtered, washed with 100ml of water:acetone 1:1, and dried at 40°C.
45 g of cephalexin hydrate was obtained.
K.F.＝5.8％
［α］D＝＋156゜（on dry base）
微生物学的titer 928mcｇ／mg
収量 82％（７−ADCAに対し）
実施例 ８
(a) エトキシカルボニルＤ−α−（１−カルボメ
トキシプロペニル）アミノフエニルアセテイト
の調製
実施例７の(a)に述べられたと同じ方法と同じ量
の反応物質が用いられた。 KF = 5.8% [α] D = +156° (on dry base) Microbiological titer 928mcg/mg Yield 82% (relative to 7-ADCA) Example 8 (a) Ethoxycarbonyl D-α-(1-carbomethoxy Preparation of propenyl)aminophenyl acetate The same method and the same amounts of reactants as described in Example 7(a) were used.
(b) ７−ADCAの溶解
130mlのDMSOのかわりに120mlのDMFを用い
ることを除いて、実施例７の(b)で述べたと同じ方
法と同じ量の反応物質が用いられた。(b) Dissolution of 7-ADCA The same method and the same amounts of reactants were used as described in Example 7 (b), except that 120 ml of DMF was used instead of 130 ml of DMSO.
(c) セフアレキシンジメチルホルムアミドソルベ
イト
(a)で調整し−55％に冷却した混合無水物のサス
ペンジヨンを、(b)で調製した７−ADCAの溶液
と素早く混合した。発熱は−30％以内であり、こ
の混合物を次いで−30℃で１時間反応させた。
TLCを行い、未反応７−ADCAの不存在が示さ
れた。温度を０℃に上げ、次いでエナミンの加水
分解を37％塩酸の溶液を加えてPH2.2にすること
によつて始めた。一定のPH2.2で加水分解が完了
した後、200mlのメチレンクロライドを加え、次
いで10分間撹拌し、30分間デカントした。メチレ
ンクロライドとアセトンを含む下層を廃棄し、他
方HPLCを濃水の上層に行い、セフアレキシン−
水和物として96％の変換が示された。この水層に
次いで250mlのDMFと100mlのアセトンを加え、
30℃に加熱してTEAの添加を始め、PH５にした。
0.5ｇのセフアレキシンDMFソルベイトを加え生
成物が結晶化された。30分後、TEAを再び加え
PH７とし、30℃で２時間後生成物を過し、100
mlのDMF：H2O9：１の溶液で洗浄み、次いでア
セトンで、そして最後に40℃で乾燥した。56.7ｇ
のセフアレキシンDMFソルベイトが得られた。(c) Cephalexin dimethylformamide sorbate The mixed anhydride suspension prepared in (a) and cooled to -55% was quickly mixed with the solution of 7-ADCA prepared in (b). The exotherm was within -30% and the mixture was then allowed to react at -30°C for 1 hour.
TLC was performed and showed the absence of unreacted 7-ADCA. The temperature was raised to 0° C. and the hydrolysis of the enamine was then started by adding a solution of 37% hydrochloric acid to a pH of 2.2. After the hydrolysis was completed at a constant pH of 2.2, 200 ml of methylene chloride was added, then stirred for 10 minutes and decanted for 30 minutes. The lower layer containing methylene chloride and acetone was discarded, while HPLC was performed on the upper layer of concentrated water to remove cephalexin.
A conversion of 96% was shown as a hydrate. Next, add 250 ml of DMF and 100 ml of acetone to this aqueous layer.
The mixture was heated to 30°C and TEA addition was started to reach a pH of 5.
The product was crystallized by adding 0.5 g of cephalexin DMF sorbate. After 30 minutes, add TEA again
The pH was adjusted to 7, and after 2 hours at 30℃, the product was filtered at 100℃.
ml DMF:H 2 O 9:1 solution, then acetone and finally drying at 40°C. 56.7g
of cephalexin DMF sorbate was obtained.
K.F.＝1.3％
［α］D＝＋110゜（on dry base）
DMF（G.L.C）＝16％
(d) セフアレキシン−水和物
上述で得られたセフアレキシンDMFソルベイ
トを０℃に冷却した150mlのH2Oに５ｇづつ加え
た。添加が終つて、300mlのアセトンを加え０℃
に３時間結晶化させた。得られた生成物を過
し、200mlのH2O：アセトン１：１混合物で、次
いでアセトンで洗浄した生成物を40℃で乾燥し、
44.2ｇのセフアレキシン−水和物が得られた。 KF = 1.3% [α] D = +110° (on dry base) DMF (GLC) = 16% (d) Cephalexin-hydrate Cephalexin DMF sorbate obtained above was cooled to 0°C and added to 150 ml of H 2 O. 5g was added to each. After addition, add 300ml of acetone and bring to 0°C.
It was crystallized for 3 hours. The product obtained was filtered and washed with 200 ml of a 1:1 mixture of H 2 O:acetone and then with acetone. The product was dried at 40 °C and
44.2 g of cephalexin hydrate was obtained.
収量 80.7％
微生物学的純度 928mcｇ／mg
K.F.＝5.5％
［α］D＝＋155゜（on dry base）
実施例 ９
(a) エトキシカルボニルＤ−α−（１−カルボメ
トキシプロペニル）アミノフエニルアセテイト
の調製
230mlの無水アセトンと43ｇ（0.15モル）のＤ
（−）フエニルグリシンのカリウムメチルデイン
ソールトを反応フラスコに入れ、−45℃に冷却し、
次いで16.7ｇ（0.1545モル）のエチルクロロフオ
ルメイトと0.3mlのＮ−メチルモルフオリンを加
えた。発熱は−25℃以内であつた。この混合物を
−25℃で２時間撹拌した。 Yield 80.7% Microbiological purity 928 mcg/mg KF=5.5% [α] D = +155° (on dry base) Example 9 (a) Ethoxycarbonyl D-α-(1-carbomethoxypropenyl) aminophenylacetate Preparation of 230 ml of anhydrous acetone and 43 g (0.15 mol) of D
(−) Phenylglycine potassium methyl deinsolate was placed in a reaction flask, cooled to −45°C,
Then 16.7 g (0.1545 mol) of ethyl chloroformate and 0.3 ml of N-methylmorpholine were added. The fever was within -25°C. This mixture was stirred at -25°C for 2 hours.
(b) ７−ADCAの溶解
80mlの脱イオンと水と32.1ｇ（0.15モル）のホ
ルムアミドを反応フラスコに入れ、15℃で16.9ｇ
（0.167モル）のTEAを15分間で７−ADCAを溶
解しながら加えた。この混合体を次いで０℃に冷
却した。(b) Dissolution of 7-ADCA 80 ml of deionized water and 32.1 g (0.15 mol) of formamide were placed in a reaction flask and 16.9 g of 7-ADCA was added at 15°C.
(0.167 mol) of TEA was added over 15 minutes while dissolving the 7-ADCA. The mixture was then cooled to 0°C.
(c) セフアレキシンホルムアミドソルベイト
(a)で調製し−55℃に冷却した混合無水物のサス
ペンジヨンを(b)で調製した７−ADCAの溶液と
素早く混合した。発熱は−25℃以内であり、この
混合物を−25℃で１時間反応させた。TLCを行
い、未反応の７−ADCAの不存在が示された。(c) Cephalexinformamide sorbate The mixed anhydride suspension prepared in (a) and cooled to -55°C was quickly mixed with the solution of 7-ADCA prepared in (b). The exotherm was within -25°C and the mixture was allowed to react at -25°C for 1 hour. TLC was performed and showed the absence of unreacted 7-ADCA.
温度を０℃に上げ、次いでエナミンの加水分解
を37％塩酸の溶液を加えてPH1.6にすることによ
つて始めた。 The temperature was raised to 0° C. and the hydrolysis of the enamine was then started by adding a solution of 37% hydrochloric acid to a pH of 1.6.
加水分解が終り一定のPH1.6で、HPLCを行い、
理論的に97％の変換が示された。この濃水はデイ
カライト（dicalite）上過し、次いで30℃に加
熱しTEAをPH５になるまで滴下した。生成物は
結晶化され、30℃で１時間放置し、次いで０℃に
冷却し、２時間後この温度で過し、アセトンで
洗浄、40℃で乾燥した。53ｇセフアレキシンホル
ムアミドソルベイトが得られた。 After hydrolysis is complete, perform HPLC at a constant pH of 1.6.
Theoretical conversion of 97% was demonstrated. This concentrated water was filtered over dicalite, then heated to 30°C and TEA was added dropwise until the pH reached 5. The product crystallized and was left at 30°C for 1 hour, then cooled to 0°C and after 2 hours filtered at this temperature, washed with acetone and dried at 40°C. 53 g of cephalexin formamide sorbate was obtained.
［α］D＝＋100゜（on dry base） K.F.＝2.1％ ホルムアミド＝10.5％（G.L.C.） このソルベイトは新規な化合物である。 [α] D = +100° (on dry base) KF = 2.1% Formamide = 10.5% (GLC) This sorbate is a new compound.
(d) セフアレキシン−水和物
上述で得られたホルムアミドソルベイトは実施
例８の(d)で述べたと同じ方法に従つてセフアレキ
シンに変換された。43.8ｇが得られた。(d) Cephalexin-hydrate The formamide sorbate obtained above was converted to cephalexin according to the same method as described in Example 8 (d). 43.8g was obtained.
収量 80％（７−ADCAに対し）
［α］D＝＋154゜（on dry base）
微生物学的titer 927mcｇ／mg
実施例 10
(a) エトキシカルボニルＤ−α−（１−カルボメ
トキシプロペニル）アミルフエニルアセテイト
の調製
250mlの無水アセトン（K.F.＝0.1％）と45.9ｇ
（0.160モル）のＤ（−）フエニルグリシンのカリ
ウムメチルデインソールトを反応フラスコに入
れ、−40℃に冷却し、次いで17.9ｇ（0.165モル）
のエチルクロロフオルメイトと0.3mlのＮ−メチ
ルモルフオリンを加えた。発熱は−35℃以内であ
つた。この混合物を次いで−35℃の温度で２時間
撹拌し、このサスペンジヨンを−50℃に冷却し
た。 Yield 80% (relative to 7-ADCA) [α] D = +154° (on dry base) Microbiological titer 927mcg/mg Example 10 (a) Ethoxycarbonyl D-α-(1-carbomethoxypropenyl) amylph Preparation of enyl acetate 250 ml of anhydrous acetone (KF = 0.1%) and 45.9 g
(0.160 mol) of potassium methyl deinsolate of D(-)phenylglycine was added to the reaction flask and cooled to -40°C, then 17.9 g (0.165 mol)
of ethyl chloroformate and 0.3 ml of N-methylmorpholine were added. The fever was within -35°C. The mixture was then stirred for 2 hours at a temperature of -35°C and the suspension was cooled to -50°C.
(b) ７−ADCAの溶解
80mlの脱イオン水次いで32.1ｇ（0.15モル）の
７−ADCAそして135mlのジメチルアセトアミド
（DMAC）を反応フラスコに入れた。15℃で16.9
ｇ（0.167モル）のTEAを加えた。７−ADCAを
溶解し、溶液のPHを約10にコントロールしなが
ら、次いで０℃に冷却した。(b) Dissolution of 7-ADCA 80 ml of deionized water was charged to the reaction flask followed by 32.1 g (0.15 mol) of 7-ADCA and 135 ml of dimethylacetamide (DMAC). 16.9 at 15℃
g (0.167 mol) of TEA was added. 7-ADCA was dissolved and the solution was cooled to 0° C. while controlling the pH of the solution to about 10.
(c) セフアレキシン−水和物の調製
実施例７の(c)で述べられたと同じ量の反応物質
を用いて同じ方法が行われた。(c) Preparation of Cephalexin-hydrate The same procedure was carried out using the same amounts of reactants as described in Example 7 (c).
43ｇのセフアレキシン−水和物が収量78.5％で
得られた。 43 g of cephalexin-hydrate was obtained with a yield of 78.5%.
K.F.＝5.85％
［α］D＝＋155゜（on dry base）
分光光計測定 98.8％
実施例 11
(a) エトキシカルボニルＤ−α−（１−カルボメ
トキシプロペニル）アミノフエニルアセテイト
の調製
220mlの無水アセトン（K.F.＝0.1％）と次いで
43ｇ（0.15モル）のＤ（−）−フエニルグリシンの
カリウムメチルデインソールトを反応フラスコに
入れ、−35℃に冷却し、16.7ｇ（0.1545モル）の
エチルクロロフオルメイトを加え、次いで0.4ml
のＮ−メチルモルフオリンを加えた。発熱は−30
℃以内であつた。この混合体を−30℃で２時間撹
拌し、−55℃冷却した。 KF=5.85% [α] D =+155° (on dry base) Spectrophotometer measurement 98.8% Example 11 (a) Preparation of ethoxycarbonyl D-α-(1-carbomethoxypropenyl)aminophenyl acetate 220 ml Anhydrous acetone (KF=0.1%) and then
43 g (0.15 mol) of potassium methyl deinsolate of D(-)-phenylglycine was placed in a reaction flask, cooled to -35°C, and 16.7 g (0.1545 mol) of ethyl chloroformate was added, followed by 0.4 ml.
of N-methylmorpholine was added. Fever is -30
It was within ℃. The mixture was stirred at -30°C for 2 hours and cooled to -55°C.
(b) ７−ADCAの溶解
80mlの脱イオン水と次いで32.1ｇ（0.15モル）
の７−ADCAと130mlのDMSOを反応フラスコに
入れた。15℃で18.75ｇ（0.185モル）のTEAを７
−ADCAを溶解しながら加えて30分撹拌後、０
℃に冷却した。(b) Dissolution of 7-ADCA 80 ml deionized water then 32.1 g (0.15 mol)
7-ADCA and 130 ml of DMSO were placed in a reaction flask. 18.75g (0.185mol) of TEA at 15℃
- Add ADCA while dissolving it and stir for 30 minutes, then 0
Cooled to ℃.
(c) セフアレキシン−水和物
実施例７の(c)で述べたと同じ方法に従いそして
同じ量の反応物質を用いて43.5ｇのセフアレキシ
ン−水和物が収量79.4％で得られた。(c) Cephalexin-hydrate Following the same procedure as described in Example 7 (c) and using the same amounts of reactants, 43.5 g of cephalexin-hydrate was obtained with a yield of 79.4%.
微生物学的titer 928mcｇ／mg
K.F.＝6.3％
実施例 12
(a) エトキシカルボニルＤ−α−（１−カルボメ
トキシプロペニル）アミノフエニルアセテイト
実施例11の(a)で述べたと同じ量の反応物質を用
いて同じ方法を行つた。この混合無水物のサスペ
ンジヨンを−50℃に冷却した。 Microbiological titer 928mcg/mg KF=6.3% Example 12 (a) Ethoxycarbonyl D-α-(1-carbomethoxypropenyl)aminophenyl acetate Same amount of reactants as mentioned in Example 11 (a) The same method was performed using The mixed anhydride suspension was cooled to -50°C.
(b) ７−ADCAの溶解
85mlの脱イオン水と次いで32.1ｇ（0.15モル）
の７−ADCAと135mlのジメチルアセトアミドを
反応フラスコに入れた。15℃で16.2ｇ（0.160モ
ル）のトリエチルアミンの添加を始めた。この添
加は10分間で終り、PHは約10で７−ADCAの溶
解が完了した。得られた溶液は０℃に冷却した。(b) Dissolution of 7-ADCA 85 ml deionized water then 32.1 g (0.15 mol)
7-ADCA and 135 ml of dimethylacetamide were placed in a reaction flask. Addition of 16.2 g (0.160 moles) of triethylamine was started at 15°C. This addition was completed in 10 minutes, and the pH was approximately 10, and the dissolution of 7-ADCA was completed. The resulting solution was cooled to 0°C.
(c) セフアレキシン−水和物
実施例７の(c)で述べたと同じ量の反応物質を用
いて同じ方法が行われた。(c) Cephalexin-hydrate The same procedure was carried out using the same amounts of reactants as described in Example 7 (c).
44.2ｇのセフアレキシン−水和物が収量80.7％
で得られた。 44.2g of cephalexin-hydrate, yield 80.7%
Obtained with.
［α］D＝＋155゜（on dry base）
K.F.＝6.5％
上述の総ての実施例において溶媒は７−
ADCAを溶解するために用いられた。もし、溶
媒が７−ADCAの溶解よりもむしろ混合無水物
の溶解に用いられるならば、述べた通りの同じ方
法に従つても、最終生成物の収量の非常に大きい
低下となる。 [α] D = +155° (on dry base) KF = 6.5% In all the above examples, the solvent was 7-
Used to dissolve ADCA. If the solvent is used to dissolve the mixed anhydride rather than the 7-ADCA, there will be a much greater reduction in the yield of the final product, even if the same method as described is followed.
上述の実施例に従つて、下記の分析的特性を有
するセフアレキシン−水和物が得られた。 According to the above examples, cephalexin-hydrate was obtained with the following analytical characteristics.
外観：白色結晶状粉末
I.R.：スタンダードと一致
水分KF：6.1％
PH 100mg／ml：4.2
Jodometric titer：99.2％（on anhydrons
materil）
分光光度測定：98.8％（ 〃 ）
H.P.L.C.titer：98.5％（ 〃 ）
酸滴定：100.8％（ 〃 ）
アミノ滴定：99.2％（ 〃 ）
施光度［α］D：＋155゜（ 〃 ）
微生物学的 titer：932mcｇ／mg
毒性：無毒
安定性（65℃／７日間）：920mcｇ／mg
溶媒（GLC）
ジメチルアニリン：検出せず
メチレンクロライド：0.04％
TEA：0.05％
［発明の効果］
以上の様に、本発明の製造方法によれば、高収
率で、しかも高純度の７−ADCAの誘導体が得
られるため、工業的に非常に有利である。Appearance: White crystalline powder IR: Consistent with standard Moisture KF: 6.1% PH 100mg/ml: 4.2 Jodometric titer: 99.2% (on anhydrons
Spectrophotometry: 98.8% (〃) HPLCtiter: 98.5% (〃) Acid titration: 100.8% (〃) Amino titration: 99.2% (〃) Light intensity [α] D : +155° (〃) Microbiological titer : 932mcg/mg Toxicity: Non-toxic Stability (65℃/7 days): 920mcg/mg Solvent (GLC) Dimethylaniline: Not detected Methylene chloride: 0.04% TEA: 0.05% [Effects of the invention] As described above, this invention According to the production method of the invention, a highly purified 7-ADCA derivative can be obtained in high yield, and therefore it is very advantageous industrially.
Claims (1)
ミド、ホルムアミド及びジメチルホルムアミドか
ら選ばれる一種を溶媒とし、水の存在下、０℃〜
20℃の温度で、７−アミノ−デスアセトキシ−セ
フアロスポラニツク酸（以下７−ADCAと略称
する）を７−ADCA1molに対し1.05〜1.25molの
トリエチルアミンで処理して得られた溶液に、構
造式（） 式中、Ｒは−Ｈまたは−OHであり、R1はメチ
ル、エチルまたはイソブチルであり、そして
R2はメトキシルまたはエトキシルである。 を有する、少なくとも７−ADCAと等mol量の混
合無水物を加えこの混合後の温度が−60℃〜−10
℃になるように維持し、次にこの反応混合体に無
機酸の水溶液を加えてPHを0.8〜2.5に下げてエナ
ミン基を分離し、最終生成物を既知の方法で分離
する事を特徴とする構造（） （式中Ｒは−Ｈまたは−OHである） を有する７−ADCAの誘導体の製造方法。 ２ ７−ADCAの溶媒が、７−ADCA1molに対
し10〜25molである特許請求の範囲第１項記載の
７−ADCAの誘導体の製造方法。[Claims] 1. Using one selected from dimethyl sulfoxide, dimethylacetamide, formamide, and dimethylformamide as a solvent, in the presence of water, from 0°C to
At a temperature of 20°C, the structure formula() where R is -H or -OH, R1 is methyl, ethyl or isobutyl, and
R 2 is methoxyl or ethoxyl. At least 7-ADCA and an equimolar amount of mixed anhydride having
℃, then add an aqueous solution of an inorganic acid to this reaction mixture to lower the pH to 0.8-2.5 to separate the enamine group, and the final product is separated by known methods. structure() (In the formula, R is -H or -OH) A method for producing a derivative of 7-ADCA. 2. The method for producing a 7-ADCA derivative according to claim 1, wherein the amount of the 7-ADCA solvent is 10 to 25 mol per 1 mol of 7-ADCA.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT27962/79A IT1126544B (en) | 1979-12-07 | 1979-12-07 | PROCEDURE FOR THE PREPARATION OF 7-AMINO-DESACETOXY CEPHALOSPORANIC ACID DERIVATIVES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS5683492A JPS5683492A (en) | 1981-07-08 |
| JPH034555B2 true JPH034555B2 (en) | 1991-01-23 |
Family
ID=11222690
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4701280A Granted JPS5683492A (en) | 1979-12-07 | 1980-04-11 | Manufacture of 77aminodesacetoxycephalosporanic acid derivative |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US4299955A (en) |
| JP (1) | JPS5683492A (en) |
| KR (1) | KR830002454B1 (en) |
| CH (1) | CH645647A5 (en) |
| DE (1) | DE3012669A1 (en) |
| FR (1) | FR2470771A1 (en) |
| GB (1) | GB2064511B (en) |
| IT (1) | IT1126544B (en) |
| NL (1) | NL191239C (en) |
| YU (1) | YU125780A (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1532682A (en) * | 1976-04-27 | 1978-11-22 | Bristol Myers Co | Process for the preparation of cephadroxil |
| ES8101078A1 (en) * | 1980-02-05 | 1980-12-16 | Liofilizaciones Esterilizacion | Water soluble cephadroxyl salt |
| YU44832B (en) * | 1981-08-03 | 1991-04-30 | Pliva Pharm & Chem Works | Process for preparing semisynthetic cephalosporins |
| HU221200B1 (en) * | 1990-01-22 | 2002-08-28 | Biochemie Gmbh | Process for producing beta-lactames |
| GB9115203D0 (en) * | 1991-07-15 | 1991-08-28 | Biochemie Gmbh | Improvements in or relating to beta lactam production |
| GB9423459D0 (en) * | 1994-11-21 | 1995-01-11 | Biochemie Gmbh | Silylation process |
| US5908929A (en) * | 1996-12-05 | 1999-06-01 | Vitara Chemicals Limited | Process for the manufacture of the antibiotic 7-(D-α-amino-α-phenylacetamido)-3-methyl-3-cephem-4-carboxylic acid (cephalexin) and pharmaceutically acceptable salts thereof |
| US20040077849A1 (en) * | 2002-10-16 | 2004-04-22 | Orchid Chemicals & Pharmaceuticals Limited | Process for the preparation of cefadroxil |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4962494A (en) * | 1972-09-15 | 1974-06-17 | ||
| JPS5040588A (en) * | 1973-07-19 | 1975-04-14 | ||
| JPS5069092A (en) * | 1973-07-05 | 1975-06-09 | ||
| JPS5082087A (en) * | 1973-09-28 | 1975-07-03 | ||
| JPS5129489A (en) * | 1974-08-30 | 1976-03-12 | Kanebo Ltd | Penishirinrui oyobi sefuarosuhorinrui no seizoho |
| JPS5133918A (en) * | 1974-07-17 | 1976-03-23 | Nederlanden Staat | Musenchukeirinkuno hinshitsukanshisochi |
| JPS51105091A (en) * | 1975-03-12 | 1976-09-17 | Sangyo Kagaku Kenkyu Kyokai | Aminoashirukano kairyohoho |
| US3985741A (en) * | 1972-09-15 | 1976-10-12 | Bristol-Myers Company | Production of p-hydroxycephalexin |
| JPS5283490A (en) * | 1975-12-30 | 1977-07-12 | Tokyo Tanabe Co | Process for preparing 77glycylamino cephlospoline derivatives |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3502663A (en) * | 1969-04-21 | 1970-03-24 | Lilly Co Eli | Crystalline cephalosporin,method for its manufacture |
| US3531481A (en) * | 1969-04-21 | 1970-09-29 | Lilly Co Eli | Method for manufacture of crystalline cephalosporin |
| BE793191A (en) * | 1971-12-28 | 1973-06-22 | Toyama Chemical Co Ltd | PROCESS FOR PRODUCING 7-ACYLAMIDO-3-CEPHEM-4- CARBOXYLIC ACIDS |
| NL162387C (en) * | 1977-09-06 | 1980-05-16 | Gist Brocades Nv | PROCESS FOR PREPARING 6- (D-ALPHA-AMINO-P- HYDROXYPHENYLACETAMIDO) PENICILLANIC ACID. |
| AT363594B (en) * | 1978-02-01 | 1981-08-10 | Biochemie Gmbh | METHOD FOR PRODUCING A NEW FORMAMIDE COMPLEX OF 7-BETA- (D-2-AMINO-2-PHENYLACETAMIDO) -3-METHYLCEPH-3-EMCARBONIC ACID |
-
1979
- 1979-12-07 IT IT27962/79A patent/IT1126544B/en active
-
1980
- 1980-03-24 US US06/132,761 patent/US4299955A/en not_active Expired - Lifetime
- 1980-04-01 DE DE19803012669 patent/DE3012669A1/en active Granted
- 1980-04-07 KR KR1019800001443A patent/KR830002454B1/en not_active IP Right Cessation
- 1980-04-11 JP JP4701280A patent/JPS5683492A/en active Granted
- 1980-05-12 YU YU01257/80A patent/YU125780A/en unknown
- 1980-05-12 GB GB8015590A patent/GB2064511B/en not_active Expired
- 1980-05-23 FR FR8011568A patent/FR2470771A1/en active Granted
- 1980-05-29 CH CH417780A patent/CH645647A5/en not_active IP Right Cessation
- 1980-11-21 NL NL8006367A patent/NL191239C/en not_active IP Right Cessation
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS4962494A (en) * | 1972-09-15 | 1974-06-17 | ||
| US3985741A (en) * | 1972-09-15 | 1976-10-12 | Bristol-Myers Company | Production of p-hydroxycephalexin |
| JPS5069092A (en) * | 1973-07-05 | 1975-06-09 | ||
| JPS5040588A (en) * | 1973-07-19 | 1975-04-14 | ||
| JPS5082087A (en) * | 1973-09-28 | 1975-07-03 | ||
| JPS5133918A (en) * | 1974-07-17 | 1976-03-23 | Nederlanden Staat | Musenchukeirinkuno hinshitsukanshisochi |
| JPS5129489A (en) * | 1974-08-30 | 1976-03-12 | Kanebo Ltd | Penishirinrui oyobi sefuarosuhorinrui no seizoho |
| JPS51105091A (en) * | 1975-03-12 | 1976-09-17 | Sangyo Kagaku Kenkyu Kyokai | Aminoashirukano kairyohoho |
| JPS5283490A (en) * | 1975-12-30 | 1977-07-12 | Tokyo Tanabe Co | Process for preparing 77glycylamino cephlospoline derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2470771B1 (en) | 1984-04-27 |
| GB2064511B (en) | 1983-06-22 |
| IT1126544B (en) | 1986-05-21 |
| DE3012669C2 (en) | 1991-05-08 |
| DE3012669A1 (en) | 1981-06-11 |
| FR2470771A1 (en) | 1981-06-12 |
| NL191239B (en) | 1994-11-01 |
| CH645647A5 (en) | 1984-10-15 |
| NL191239C (en) | 1995-04-03 |
| IT7927962A0 (en) | 1979-12-07 |
| US4299955A (en) | 1981-11-10 |
| KR830002454B1 (en) | 1983-10-26 |
| YU125780A (en) | 1983-04-30 |
| KR830002774A (en) | 1983-05-30 |
| NL8006367A (en) | 1981-07-01 |
| GB2064511A (en) | 1981-06-17 |
| JPS5683492A (en) | 1981-07-08 |
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